US3360435A - Treatment of depressed states - Google Patents

Treatment of depressed states Download PDF

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Publication number
US3360435A
US3360435A US457837A US45783765A US3360435A US 3360435 A US3360435 A US 3360435A US 457837 A US457837 A US 457837A US 45783765 A US45783765 A US 45783765A US 3360435 A US3360435 A US 3360435A
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US
United States
Prior art keywords
phenylindene
dimethylaminoethyl
hydrochloride
reserpine
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US457837A
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English (en)
Inventor
Kandel Alexander
Lish Paul Merrill
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mead Johnson and Co LLC
Original Assignee
Mead Johnson and Co LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mead Johnson and Co LLC filed Critical Mead Johnson and Co LLC
Priority to US457837A priority Critical patent/US3360435A/en
Priority to GB28248/65A priority patent/GB1041989A/en
Priority to IL23869A priority patent/IL23869A/en
Priority to ES0315465A priority patent/ES315465A1/es
Priority to SE9813/65A priority patent/SE322770B/xx
Priority to DE19651543216 priority patent/DE1543216B1/de
Priority to BR171638/65A priority patent/BR6571638D0/pt
Priority to CH1114968A priority patent/CH473760A/de
Priority to CH1068665A priority patent/CH463486A/de
Priority to BE667739D priority patent/BE667739A/xx
Priority to NL6509895A priority patent/NL6509895A/xx
Priority to FR26747A priority patent/FR4646M/fr
Priority to AT707165A priority patent/AT267511B/de
Priority to FR26746A priority patent/FR1482826A/fr
Application granted granted Critical
Publication of US3360435A publication Critical patent/US3360435A/en
Priority to SE08871/68A priority patent/SE332171B/xx
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16B—DEVICES FOR FASTENING OR SECURING CONSTRUCTIONAL ELEMENTS OR MACHINE PARTS TOGETHER, e.g. NAILS, BOLTS, CIRCLIPS, CLAMPS, CLIPS OR WEDGES; JOINTS OR JOINTING
    • F16B12/00—Jointing of furniture or the like, e.g. hidden from exterior
    • F16B12/44—Leg joints; Corner joints
    • F16B12/48—Non-metal leg connections

Definitions

  • reserpine antagonism tests The measurement of antidepressant effects in the laboratory is accomplished by means of a group of tests referred to generally as reserpine antagonism tests.
  • One of the effects of reserpine on which its pharmacologic use is based is its ability to induce a depressed state.
  • concomitant pharmacologic or physiologic effects are exerted, including hypothermia, ptosis, and miosis.
  • Antidepressant drugs such as imipramine and amitriptyline have the capacity to prevent these physiological effects.
  • a predetermined dose of test compound is administered orally to each mouse of several groups of test mice.
  • reserpine 2.0 mg./kg.
  • ptosis is measured by placing each mouse on a platform away from light and estimating the extent of closure of the palpebral fissure.
  • Ptosis is significant if the opening is not greater than 50% of normal.
  • the reserpine effect is significantly modified if the palpebral opening is greater than 50% of normal.
  • the reduction of rectal temperature following reserpine is used as a parameter. Reserpine alone produces a significant reduction of rectal temperature in mice. Antidepresant drugs will prevent this effect.
  • Antidepressant drugs can be distinguished from psychostimulan-t drugs such as amphetamine by reversing the order of administration in the above test. That is, by administering reserpine first followed by the test drug, the extent of reversal of reserpine effect can be determined.
  • Psychostimulants characteristically have the ability to reverse the reserpine effects, while the antidepressants do not. That is, the antidepressants will prevent but not reverse the reserpiue effects in mice.
  • the above tests are conducted according to accepted pharmacological technique, by administering various doses of drug-s to groups of test animals and then conexhibits an ED value of 10 mg./-kg., while I-(Z-dimethylaminoethyl) l-phenylindene hydrochloride exhibits ED value for the prevention of reserpine ptosis in mice administration of I-(Z-dimethylaminoethyl) l-phenylindene hydrochloride elicits a truly outstanding antireserpine effect in animals characterizing the material as an antidepressant agent.
  • PREPARATION 1-(2-dimethylaminoethyl) l-phenylindene is prepared from 3-phenylindene by alkylation thereof with a 2-dimethylaminoethyl halide such as the bromide, chloride or iodide or other alkylating agent capable of introducing the Z-dime-thylaminoethyl group.
  • a 2-dimethylaminoethyl halide such as the bromide, chloride or iodide or other alkylating agent capable of introducing the Z-dime-thylaminoethyl group.
  • alkylating agent is a reactive ester of Z-dimethylaminoethanol such as the ester with p-toluenesulfonic acid.
  • the alkylation of 3-phenylindene with a Z-dimethylaminoethyl halide or other reactive ester of Z-dimethylaminoethanol is conducted on an alkali metal salt of3- phenylindene.
  • the intermediate alkali metal salt is prepared by reaction of 3-phenylindene with a strong base such as sodium amide, sodium hydride, lithium amide, butyl lithium, sodium triphenylmethyl, or others.
  • the alkali metal salt of 3-phenylindene is preferably prepared in situ and allowed to react with the Z-dimethylaminoethyl halide without isolation. For this reason, the alkali metal base employed for salt formation may be looked upon simply as a condensing agent for the reaction between 3-phenylindene and Z-dimethylarninoethyl halide.
  • the mixture may contain dialkylated products as well.
  • This mixture of products can be separated by conventional methods, including distillation and fractional crystallization of acid addition salts thereof from appropriate solvents and solvent mixtures.
  • the individal pure products can then be unequivocally identified by interpretation of their nuclear magnetic resonance spectra.
  • Compound I is one of the active agents used in the antidepressant process of the present invention.
  • Compound II is substantially inactive.
  • Compound II may exist as an isomer or mixture of isomers where the double bond is in either the 1,2-position or in the 2,3-position, as is indicated by the dotted line and double headed arrow in the above formula.
  • PROCEDURE 3-phenylindene 76.8 g., is dissolved in 150 ml. of ether and treated with 0.4 mole of freshly prepared butyl lithium solution while protected from atmospheric moisture by dry nitrogen gas. A temperature of 20-30" C. is maintained during the addition of the butyl lithium solution, after which the solution is refluxed for /2 hour.
  • the reaction mixture is then diluted with 200 ml. of ether and added to a solution of 0.5 mole of fl-dimethylaminoethyl chloride in 100 ml. of ether.
  • a further reflux period of 2 hours is then commenced, after which the reaction mixture is allowed to cool and then extracted with 200 ml. of 6N-hydrochloric acid.
  • the aqueous layer is separated, basified, and extracted with ether.
  • the ether extracts are dried, the solvent removed by distillation, and the residue distilled in vacuo, B.P. l54163/0.2 mm., 11 1.5906,
  • the pure free base 1-(Z-dimethylaminoethyl)-1-phenylindene may be obtained by treatment of the pure hydrochloride salt having the physical constants listed above with a solution of a strong alkali such as aqueous sodium hydroxide.
  • the pure free base obtained in this fashion has the following properties:
  • Any desired pharmaceutically acceptable acid addition salt may be obtained by direct neutralization of the free base with the appropriate acid. Purification of the free base to the extent referred to above is not necessary for this purpose. If a crude form of the base is employed, care should be taken to characterize the salt formed therefrom, for instance, by nuclear magnetic resonance studies, as having the structure of Compound I.
  • Pharmaceutically acceptable acid addition salts are those in which the anion does not contribute significant toxicity to the salt in the dosages thereof employed in accordance with the present invention.
  • suitable salts are the acetate, propionate, butyrate, pamoate, tannate, mucate, citrate, malate, tosylate, mesylate phosphate, nitrate, sulfate, hydrobromide, hydroiodide, hydrochloride, etc.
  • the hydrochloride salt described above is soluble in water at room temperature to the extent of by weight. It is also soluble in ethanol and in warm isopropanel from which it crystallizes on cooling. It is stable in aqueous solution.
  • the 1-[2-(methylamino)ethyl] 1 phenylindene may be prepared from Compound I by demethylation with alkyl haloformate followed by hydrolysis and decarboxylation as shown in the following equation:
  • the demethylation step proceeds best at temperatures of from to 150 C.
  • the 1-[2-(methylamino)ethyl]-l-phenyl indene may be prepared by reacting the l-phenyl indene salt with a N-(2-haloethyl)-N-rnethyl carbamic acid ester of the formula where X and R are as above defined to produce Compound III directly as above shown.
  • the further steps of hydrolysis and decarboxylation are as in the above equation and in the procedure following.
  • the benzene layer is then dried over potassium carbonate, the drying agent removed, and the solvent evaporated in vacuo.
  • the residual 1-[2-(N-carbethoxy-N-methyl) aminoethyl1-1-phenylindene is then refluxed for 10 hours with a solution of 6 g. of potassium hydroxide in 25 ml. of aqueous ethanol.
  • the reaction mixture is cooled, diluted with benzene, and extracted with three 5 ml. portions of water.
  • the mixture is dried over potassium carbonate, and the product recovered from the extract by evaporation as before.
  • the residue is dissolved in ether and treated with hydrogen chloride, resulting in precipitation of the desired product.
  • This material is recrystallized first from an ethylacetate-acetonitrile mixture, and then from acetone, M.P. 176-178 C.
  • Infrared absorption maxima are observed at the following wave lengths: 3030; 2930; 2760; 2428; 1588; 8; 790, 769, 754, 732 and 699 cmf
  • DOSAGE Toxicity studies were conducted in mice of the Swiss- W ebster strain weighing 18 to 25 g. and treated orally with 10 mL/kg. of body weight of an aqueous solution 75 containing varying doses of 1-(Z-dimethylaminoethyl)-1- phenyl-l-indene hydrochloride at a pH of 4.0-5.5 by intubation. The animals were observed for signs of side effects and the number of deaths occurring within 24 hours was recorded. Dose response curves Were prepared.
  • the dose eliciting detectable side effect in 50% of the animals was found to be 14 mg./kg. and the dose resulting in death of 50% of the animals (LD was found to be 84 mg./ kg.
  • Side effects observed included hype activity, increased respiratory depth, and ataxia.
  • the intraperitonea l LD in the mouse is 52.5 mg./kg.
  • the oral LD in the rat is 385 mg./kg.
  • the intravenous LD in the dog is estimated to be about 30 mg./kg.
  • the effective antidepressant dosage range for l-(2-dimethylaminoethyl) 1 phenylindene hydrochloride and l- [2- (methylamino) ethyl] -1-phenylindene hydrochloride in the process of the present invention is from about 0.1 mg. to about 5 mg./kg. of body weight of the animal being treated.
  • no side effects such as mydriasis, lack of salivation, or other side effects which are frequently manifested by the secondary pharmacologic properties of prior antidepressant drugs are observed.
  • Dosage according to the present invention may be by either the oral or parenteral routes. In the ordinary case, the oral route is preferred as a matter of convenience, but occasionally when this method of dosage cannot be accomplished due to idiosyncrasy, parenteral administration is satisfactory and preferred.
  • Solution for injection A sterile aqueous solution having a concentration of 25 mg./m1. of l-(2-dimethylaminoethyl)-1-phenylindene hydrochloride is prepared by dissolving 25 g. of the substance in 9 l. of water for injection, U.S.P., adjusting to pH 5.5 with dilute aqueous sodium hydroxide, and dilution to 10 1. This solution is then filtered sparkling clear and filled into 2 ml. glass ampoules and sealed. The ampoules are then sterilized by heating.
  • Capsules-A dry blend of 5.0 g. of 1-(2-dimethylaminoethyl)-1-phenylindene hydrochloride, 19.8 g. of lactose, and 0.2 g. of magnesium stearate is prepared. This mixture is then employed to fill No. 2 hard gelatin capsules, each with 250 mg. of the blend.
  • the process of eliciting an antidepressant effect in a host subject to a depressed condition which comprises administering to said host a dose of from 0.1 to 5 rug/kg. of body weight of said host of a compound selected from the group consisting of l-(2-dimethylaminoethyl)-1-phenylindene, 1-[2-(methyla1mino)ethyl]-1- pbenylidene and the pharmaceutically acceptable acid addition salts thereof.

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  • Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Mechanical Engineering (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US457837A 1964-09-15 1965-05-21 Treatment of depressed states Expired - Lifetime US3360435A (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
US457837A US3360435A (en) 1964-09-15 1965-05-21 Treatment of depressed states
GB28248/65A GB1041989A (en) 1964-09-15 1965-07-02 A process of preparing 1-(2-dimethylaminoethyl)-1-phenylindene and 1-[2-(methylamino) ethyl]-1-phenylindene
IL23869A IL23869A (en) 1964-09-15 1965-07-02 1 -) 2 - Dimethylaminoethyl (- 1 - phenylindene and 1 -] 2 -) methyl - amino (ethyl [- 1 - phenylindene
ES0315465A ES315465A1 (es) 1964-09-15 1965-07-17 Un procedimiento para preparar compuestos con propiedades estimulantes del sistema nervioso.
SE9813/65A SE322770B (xx) 1964-09-15 1965-07-26
DE19651543216 DE1543216B1 (de) 1964-09-15 1965-07-27 Verfahren zur Herstellung von 1-(2'-Dimethylaminoaethyl)-1-phenylinden und 1-(2'-Methylaminoaethyl)-1-phenylinden
BR171638/65A BR6571638D0 (pt) 1964-09-15 1965-07-28 Um processo para preparar 1-(2-dimetil-amino-etil) 1-fenil indeno e 1-(2-metil amino eti1)-1-fenil-indeno
CH1068665A CH463486A (de) 1964-09-15 1965-07-29 Verfahren zur Herstellung von 1-(2-Dimethyl-aminoäthyl)-1-phenylinden
CH1114968A CH473760A (de) 1964-09-15 1965-07-29 Verfahren zur Herstellung von 1-(2-Methylaminoäthyl)-1-phenylinden
BE667739D BE667739A (xx) 1964-09-15 1965-07-30
NL6509895A NL6509895A (xx) 1964-09-15 1965-07-30
FR26747A FR4646M (xx) 1964-09-15 1965-07-30
AT707165A AT267511B (de) 1965-05-21 1965-07-30 Verfahren zur Herstellung neuer 1-Phenyl-1-(2'-aminoäthyl)-indene und ihrer Salze
FR26746A FR1482826A (fr) 1964-09-15 1965-07-30 Procédé de préparation des composés du groupe comprenant le 1-(2-diméthylaminoéthyl)-1-phénylindène, le 1-[2-(méthylamino)-éthyl]-1-phénylindène et leurs sels d'addition d'acides
SE08871/68A SE332171B (xx) 1964-09-15 1968-06-28

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US39767364A 1964-09-15 1964-09-15
US457837A US3360435A (en) 1964-09-15 1965-05-21 Treatment of depressed states

Publications (1)

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US3360435A true US3360435A (en) 1967-12-26

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US457837A Expired - Lifetime US3360435A (en) 1964-09-15 1965-05-21 Treatment of depressed states

Country Status (11)

Country Link
US (1) US3360435A (xx)
BE (1) BE667739A (xx)
BR (1) BR6571638D0 (xx)
CH (2) CH463486A (xx)
DE (1) DE1543216B1 (xx)
ES (1) ES315465A1 (xx)
FR (2) FR1482826A (xx)
GB (1) GB1041989A (xx)
IL (1) IL23869A (xx)
NL (1) NL6509895A (xx)
SE (2) SE322770B (xx)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE371190B (xx) * 1972-03-24 1974-11-11 Kabi Ab

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB959704A (en) * 1961-08-31 1964-06-03 Smith Kline French Lab New indene derivatives and method of preparing the same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2798888A (en) * 1952-08-12 1957-07-09 Ciba Pharm Prod Inc Indene and indane compounds and their production

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB959704A (en) * 1961-08-31 1964-06-03 Smith Kline French Lab New indene derivatives and method of preparing the same

Also Published As

Publication number Publication date
GB1041989A (en) 1966-09-07
CH463486A (de) 1968-10-15
ES315465A1 (es) 1966-06-01
SE332171B (xx) 1971-02-01
BE667739A (xx) 1966-01-31
FR1482826A (fr) 1967-06-02
IL23869A (en) 1970-09-17
DE1543216B1 (de) 1972-11-09
BR6571638D0 (pt) 1973-08-14
NL6509895A (xx) 1966-03-16
CH473760A (de) 1969-06-15
SE322770B (xx) 1970-04-20
FR4646M (xx) 1966-12-05

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